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New Treatments for Breast Cancer


Management of Ductal Carcinoma In Situ

The optimal management of ductal carcinoma in situ (DCIS) of the breast is one of the greatest challenges in breast disease faced by clinicians today. Ductal carcinoma in situ  comprises 20% to 40% of all mammogram-directed biopsies. The National Cancer Database reports that DCIS comprised 7% of all newly diagnosed breast cancers in 1985.

Confusion surrounding the optimal treatment of DCIS continues. Ductal carcinoma in situ is not life-threatening per se unless it progresses to invasive cancer. DCIS may, however, be treated even more aggressively (i.e., with mastectomy) than might be recommended for invasive

Natural History of Ductal Carcinoma In Situ

Undoubtedly, the improved availability of mammographic screening has dramatically increased the detection rate of DCIS, resulting in an earlier and possibly overly aggressive intervention at this stage of breast cancer. Autopsy series suggest that the prevalence of undetected DCIS is close to 9% in the overall population, and it is likely that many of these lesions can remain undetected and be clinically insignificant for many decades. The consequences of treating DCIS by observation alone are unclear.

Indirect evidence pertaining to the natural history of DCIS can be obtained from early studies examining the long-term recurrence rates in women treated for DCIS with biopsy only. Page and Dupont reported a small series of 28 women who had undergone surgery.

These studies demonstrate that low-grade DCIS also progresses to invasive cancer but do not elucidate which patients are at highest risk for progression to more aggressive disease. What is clear, however, is that the risk of developing invasive cancer may persist even two decades after diagnosis of DCIS if an initial complete excision is not performed. One of the most challenging areas for research and intervention will be to identify those factors responsible.


Treatment Considerations and Management of Ductal Carcinoma In Situ

Surgery

Mastectomy

The recurrence rate following mastectomy for DCIS has been shown to be between 0 and 2% on long-term follow-up. There is thus no role for adjuvant irradiation following mastectomy for DCIS. This procedure remains the standard against which the outcomes of all other therapy must be compared but is the most aggressive of the treatment options.

Breast Conservation

The widespread successful use of breast-conserving treatment for invasive cancer has focused efforts to identify which women with DCIS may be appropriately treated with wide excision rather than mastectomy.

Technical Considerations and Recommendations

Wide excision for DCIS is appropriate in patients with limited extent of disease. Careful attention must be paid to the margin status, although intraoperative decision-making is hampered because intraductal lesions are for the most part not distinguishable from normal surrounding tissue. Precise anatomic orientation is critical in identifying the location of any positive margins.

Axillary Lymph Node Dissection

Current data indicate that the incidence of axillary lymph node metastases in pure DCIS is 0 to 1%, obviating the need for axillary dissection in these patients. For complicated cases with an associated mass and questions of microscopic invasion, axillary lymph node dissection.

The Role of Adjuvant Radiation

The role of irradiation in the treatment of DCIS continues to evolve. Many studies have now conclusively demonstrated approximately a 50% reduction in local recurrence with the addition of radiotherapy to surgical excision. The most compelling data come from The National Surgical Adjuvant Breast and Bowel Project trial (NSABP) B-17, a prospective trial that randomly assigned 818 patients to surgery only or to surgery plus irradiation. The most recent update of this study, with a mean follow-up of 90 months, shows a reduction in noninvasive ipsilateral breast tumors (IBT) from 13.4% to 8.2% ( P = 0.007), with a similar reduction in invasive IBT from 13.4% to 3.9% ( P = < 0.0001).

The Role of Chemoprevention

Tamoxifen

Tamoxifen, a nonsteroidal compound with mixed estrogenic and antiestrogenic effects, has repeatedly shown effectiveness in decreasing recurrence rates of invasive breast cancer, particularly in women with estrogen receptor (ER)-positive tumors. Tamoxifen has also consistently demonstrated the ability to reduce the incidence of contralateral breast cancer, an observation that has led to the institution of several tamoxifen-based prevention trials. The NSABP trial (P-01), by far the largest prevention study to date, demonstrated that tamoxifen reduces the risk of developing both invasive and noninvasive breast cancer by 40%. Two other European prevention studies have not been able to demonstrate a statistically significant risk reduction, but these trials lack the statistical power of P-01.

One would anticipate that tamoxifen therapy alone could also reduce both the recurrence of DCIS and the progression of DCIS to invasive cancer following lumpectomy, even in the absence of radiation therapy, but these studies have not yet been conducted. The NSABP B-24 study found that, for the population studied, the risk of developing contralateral invasive breast cancer (CBC) was nearly as high as the risk of developing ipsilateral invasive breast cancer (IBC) after irradiation. In the placebo group, the cumulative 5-year risk of invasive CBC.

In a recent meta-analysis of the NSABP trials, the cumulative risk of CBC (both invasive and intraductal) for women with a cancer diagnosis was 5.1% after 5 years, which was reduced to 1.9% in women who took tamoxifen.

New Compounds

The deleterious side effects of tamoxifen have spurred great interest in the development of new agents that have antiestrogenic effects at the level of both breast and uterine tissue while maintaining the beneficial estrogen-like effects on bone mineral density and the cardiovascular system. This group of compounds has been termed selective estrogen receptor modulators, or SERMs, and the best studied is the agent raloxifene (marketed as Evista), which was developed to prevent osteoporosis in postmenopausal women. Raloxifene also lowers serum concentrations of total and low-density lipoprotein cholesterol and does not stimulate the endometrium.

Initially intended to be an alternative to hormone replacement therapy, raloxifene has been tested for its effect on bone mineral density and fractures but not for its effect on breast cancer. Nevertheless, some striking data were gathered from the Multiple Outcomes of Raloxifene Evaluation Study (MORE trial). In this large randomized study, 7705 postmenopausal women with osteoporosis were treated with raloxifene (60 or 120 mg/d). Raloxifene significantly reduced bone mineral density loss and the fracture rate compared with placebo.

Imaging

The most common presentation of DCIS is that of abnormal calcifications on routine screening mammography. In the NSABP B-17 randomized trial, 83% of patients had mammographic findings only. Several different patterns of calcifications suggest DCIS.
 

Predictors of Recurrence Following Treatment for Ductal Carcinoma In Situ

The recurrence rate following simple mastectomy for DCIS ranges from 0 to 2%. A critical evaluation of the factors leading to recurrence of intraductal carcinoma following mastectomy.

Family History of Breast Cancer

Few studies have been specifically designed to determine whether a history of breast cancer in a first-degree relative places a woman at increased risk of recurrence following breast-conserving surgery for DCIS. At least two reports, however, indicate that family history may have a measurable effect. In a small study of women undergoing breast-conserving surgery.

Age at Diagnosis and Menopausal Status

In studies published to date, the two variables of age and menopausal status have not been separately evaluated in multivariate analysis. In one report of 133 patients with DCIS treated with wide excision and irradiation, Silverstein found that age was not a predictor of recurrence on univariate analysis ( P = 0.3). At least three other studies, however, have demonstrated that postmenopausal status or older age confers a beneficial effect on local recurrence.